A phase 1 study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumors.

Wilson, R., Evans, J., Middleton, M., Molife, L. R., Spicer, J., Dieras, V., Roxburgh, P., Giordano, H., Jaw-Tsai , S., Goble, S., & Plummer, R. (2017). A phase 1 study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumors. British Journal of Cancer, 116(7), 884-892. https://doi.org/10.1038/bjc.2017.36 Published in: British Journal of Cancer

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British Journal of Cancer (2017) 116, 884–892 | doi: 10.1038/bjc.2017.36

Keywords: rucaparib; carboplatin; PARP inhibitor; pharmacokinetics and pharmacodynamics; breast cancer; ovarian cancer; pancreatic cancer; BRCA1, BRCA2 A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours

Richard H Wilson1,2, TR Jeffry Evans3, Mark R Middleton4, L Rhoda Molife5, James Spicer6, Veronique Dieras7, Patricia Roxburgh3, Heidi Giordano8, Sarah Jaw-Tsai8, Sandra Goble8 and Ruth Plummer*,9,10 1Centre for Cancer Research and Cell Biology, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK; 2Northern Ireland Cancer Center, Belfast City Hospital, 51 Lisburn Road, Belfast BT9 7AB, UK; 3Beatson West of Scotland Cancer Centre, and Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; 4National Institute for Health Research Biomedical Research Centre, Churchill Hospital, and Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK; 5Drug Development Unit, Royal Marsden Hospital/Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UK; 6Division of Cancer Studies, King’s College London, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK; 7Department of Medical Oncology, Institut Curie, 26, rue d’Ulm, Paris 75005 France; 8Clovis Oncology, Inc., Boulder, 5500 Flatiron Parkway, Boulder, CO 80301, USA; 9Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, High Heaton, Newcastle Upon Tyne NE7 7DN, UK and 10Northern Institute for Cancer Research, Newcastle University, Paul O’Gorman Building, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK

Background: This study evaluated safety, pharmacokinetics, and clinical activity of intravenous and oral rucaparib, a poly(ADP- ribose) polymerase inhibitor, combined with chemotherapy in patients with advanced solid tumours.

Methods: Initially, patients received escalating doses of intravenous rucaparib combined with carboplatin, carboplatin/paclitaxel, cisplatin/ pemetrexed, or epirubicin/cyclophosphamide. Subsequently, the study was amended to focus on oral rucaparib (once daily, days 1–14) combined with carboplatin (day 1) in 21-day cycles. Dose-limiting toxicities (DLTs) were assessed in cycle 1 and safety in all cycles.

Results: Eighty-five patients were enrolled (22 breast, 15 ovarian/peritoneal, and 48 other primary cancers), with a median of three prior therapies (range, 1–7). Neutropenia (27.1%) and thrombocytopenia (18.8%) were the most common grade X3 toxicities across combinations and were DLTs with the oral rucaparib/carboplatin combination. Maximum tolerated dose for the combination was 240 mg per day oral rucaparib and carboplatin area under the curve 5 mg ml 1 min 1. Oral rucaparib demonstrated dose-proportional kinetics, a long half-life (E17 h), and good bioavailability (36%). Pharmacokinetics were unchanged by carboplatin coadministration. The rucaparib/carboplatin combination had radiologic antitumour activity, primarily in BRCA1- or BRCA2-mutated breast and ovarian/peritoneal cancers.

Conclusions: Oral rucaparib can be safely combined with a clinically relevant dose of carboplatin in patients with advanced solid tumours (Trial registration ID: NCT01009190).

The poly (ADP-ribose) polymerase (PARP) family includes DNA double-strand breaks (Schreiber et al, 2006). The DNA enzymes that are involved in the repair of single-strand breaks, a double-strand breaks can be repaired by a separate process known common type of DNA damage, thus preventing the formation of as homologous recombination, mediated by BRCA1 and BRCA2

*Correspondence: Dr R Plummer; E-mail: [email protected] Received 28 July 2016; revised 14 December 2016; accepted 20 January 2017; published online 21 February 2017 r The Author(s) named above

884 Published by Springer Nature on behalf of Cancer Research UK. Phase I intravenous and oral rucaparib with chemo BRITISH JOURNAL OF CANCER

(Moynahan et al, 1999, 2001; Venkitaraman, 2002). Tumours Shapira-Frommer et al, 2015). In phase I and II studies, the harbouring a BRCA mutation or other defect in homologous combination of i.v. rucaparib and the DNA-alkylating agent recombination repair are sensitive to PARP inhibitors, because temozolomide was active in patients with advanced solid tumours cells accumulate unrepaired single-strand breaks that are converted and resulted in increased activity compared with historical data of to double-strand breaks that cannot be repaired and therefore single-agent temozolomide in patients with metastatic melanoma result in cell death (Bryant et al, 2005; Farmer et al, 2005; Helleday (Plummer et al, 2008, 2013). et al, 2007, 2008; Ashworth, 2008). Furthermore, studies have This phase I dose-escalation study evaluated rucaparib in demonstrated that PARP inhibition can interfere with the combination with several standard chemotherapeutic regimens in alternative nonhomologous end-joining DNA repair pathway that patients with advanced solid tumours, independent of BRCA is upregulated in homologous recombination-deficient cells status. The study initially explored an i.v. formulation of rucaparib; (Helleday, 2011; Ceccaldi et al, 2015; Konstantinopoulos et al, however, during the conduct of this study, an oral formulation of 2015; Mateos-Gomez et al, 2015). The PARP inhibitors can also rucaparib was developed that could be administered for a longer result in trapping of PARP-1 and PARP-2 at the site of the DNA duration, and the study was amended to evaluate the oral break, resulting in obstructed replication forks that require bioavailability of this new formulation. Once bioavailability was functional homologous recombination for repair (Helleday, 2011; established, the study was amended to evaluate oral rucaparib in Murai et al, 2012; O’Connor, 2015). combination with carboplatin. Here, we report final results from all Consistent with the role of PARPs in DNA repair, inhibiting patients enrolled in the study, with a focus on those who received PARP has been shown to increase the potency of DNA-damaging oral rucaparib in combination with carboplatin. agents, such as chemotherapy and radiotherapy (Calabrese et al, 2004; Donawho et al, 2007; Thomas et al, 2007; Ihnen et al, 2013). Preclinical data suggest that a PARP inhibitor in combination with carboplatin or cisplatin has enhanced efficacy over either agent MATERIALS AND METHODS individually in BRCA-mutated tumours (Evers et al, 2008; Drew et al, 2011; Clark et al, 2012). The synergistic effect Study design. This study was an open-label, multicentre, dose- of these combinations may be the result of an increase in DNA escalating phase I study of rucaparib administered in combination damage (e.g., intrastrand crosslinks) induced by platinum-based with one of four different standard chemotherapeutic regimens chemotherapies that requires repair through PARP-dependent (NCT01009190). Eligible patients X18 years of age had a pathways. histologically or cytologically confirmed advanced solid tumour, Rucaparib (formerly known as AG-014699 and PF-01367338) is an Eastern Cooperative Oncology Group (ECOG) Performance a potent small-molecule inhibitor of PARP-1, PARP-2, and PARP- Status of 0 or 1, life expectancy of X12 weeks, and adequate bone 3 that is being developed for the treatment of ovarian cancer and marrow, liver, and renal function. All BRCA testing was done other tumour types associated with homologous recombination locally and was not verified by the sponsor. The primary objective deficiency (HRD), including BRCA1 and BRCA2 mutations was to assess safety and tolerability and estimate the maximum (Thomas et al, 2007; Drew et al, 2011; Swisher et al, 2017). In a tolerated dose (MTD) and/or select the recommended phase II phase II study in patients with advanced ovarian or breast cancer dose of rucaparib in combination with chemotherapy. Secondary associated with a germline BRCA1/2 mutation, continuous dosing objectives were to characterise the pharmacokinetics (PK) and of single-agent oral rucaparib led to a higher rate of response than assess the antitumour activity of rucaparib when combined with intermittent intravenous (i.v.) dosing (response rate, 18% vs 2%) chemotherapy. (Drew et al, 2016). A subsequent phase I–II dose-escalation study The study was approved by the Research Ethics Committee for established the recommended phase II dose of single-agent oral all participating institutions and conducted in accordance with the rucaparib as 600 mg twice daily (Kristeleit et al, 2014) and Declaration of Helsinki and the Good Clinical Practice Guidelines demonstrated the clinical activity and manageable safety profile of of the International Conference on Harmonisation. Patients gave rucaparib in patients with advanced solid tumours, including written informed consent before undergoing any study-related BRCA-mutated ovarian and breast cancers (Kristeleit et al, 2014; procedures.

Patients with advanced solid tumours N=85

Arm A Arm B Arm C Arm D Arm A (Oral)

i.v. rucaparib + i.v. rucaparib + i.v. rucaparib + i.v. rucaparib + epirubicin + Oral rucaparib + carboplatin paclitaxel + carboplatin pemetrexed + cisplatin cyclophosphamide carboplatin n=18 n=13 n=16 n=5 n=33

Dose cohorts Dose cohorts Dose cohorts Dose cohorts Dose cohorts –2 –2 12 mg/AUC4 12 mg/140 mg m–2/AUC4 12 mg/400 mg m–2/60 mg m–2 12 mg/30 mg m /300 mg m 80 mg/AUC3 (n=4) (n=3) (n=3) (n=3) (n=5) 120 mg/AUC3 (n=4) –2 –2 12 mg/AUC5 12 mg/175 mg m–2/AUC5 12 mg/500 mg m /75 mg m 180 mg/AUC3 (n=3) (n=3) (n=6) (n=6) 240 mg/AUC3 (n=3) –2 –2 –2 18 mg/AUC5 18 mg/175 mg m /AUC5 18 mg/500 mg m /75 mg m 360 mg/AUC3 (n=3) (n=6) (n=4) (n=4) –2 –2 360 mg/AUC4 (n=3) 24 mg/AUC5 24 mg/500 mg m /75 mg m 360 mg/AUC5 (n=6) (n=6) (n=3) 240 mg/AUC5 (n=7)

Figure 1. Study treatment arms. www.bjcancer.com | DOI:10.1038/bjc.2017.36 885 BRITISH JOURNAL OF CANCER Phase I intravenous and oral rucaparib with chemo

Treatments. Patients received escalating doses of i.v. rucaparib least two of the three to six patients treated at that dose level; this (days 1–3) with standard doses of chemotherapeutic regimens. dose was then considered above the MTD and further dose Initial starting doses for each chemotherapy were as follows: escalations were stopped. When a dose was concluded to be above arm A, rucaparib (24 mg) þ carboplatin (area under the curve the MTD, the preceding lower dose was declared the MTD, but 4 mg min ml 1 (AUC4)); arm B, rucaparib (24 mg) þ carboplatin only if six patients had already been treated at this lower dose. (AUC4) þ paclitaxel (140 mg m 2); arm C, rucaparib (24 mg) þ Otherwise, three additional patients were treated at this lower dose, cisplatin (60 mg m 2) þ pemetrexed (400 mg m 2); and arm D, and if none or one of those patients had a DLT, this lower dose was rucaparib (12 mg) þ epirubicin (30 mg m 2) þ cyclophosphamide declared the MTD. (300 mg m 2) (Figure 1). Initially, patients received chemotherapy All patients who received at least one dose of study medication (day 1) and i.v. rucaparib (days 1–3) in 21-day treatment cycles. were evaluable for toxicity. Patients were considered nonevaluable However, during the conduct of the study, an oral formulation of for DLT assessments if they missed the rucaparib lead-in doses, rucaparib was developed and introduced under a protocol had administration of o80% of the planned cycle 1 doses of amendment, with an additional secondary objective to determine rucaparib, and/or had administration of o80% of the planned its absolute oral bioavailability. Subsequently, the i.v. rucaparib cycle 1 doses of chemotherapy for that dose level (provided that the arms were discontinued and three of the chemotherapy arms (B, C, reduction did not result from toxicity). and D) were closed to further enrolment. Thereafter, all enrolled Antitumour activity was assessed by the investigators according patients received oral rucaparib in combination with i.v. carbo- to Response Evaluation Criteria in Solid Tumor version 1.1 platin (arm A, oral rucaparib) (Figure 1). (RECIST) (Eisenhauer et al, 2009) through radiological tumour Treatment with rucaparib in combination with chemotherapy assessments performed every two cycles and/or at the end of was continued until progression, unacceptable toxicity, patient’s treatment, whichever occurred first. withdrawal of consent, or as deemed appropriate by the judgement of the treating physician (whichever came first). Pharmacokinetics. On cycle 1 days 10, 5, 1, and 14, plasma samples were obtained from all patients before rucaparib dosing and at 15 and 30 min, and at 1, 1.5, 2.5, 4, 6, 10, and 24 h after the Oral rucaparib in combination with carboplatin. Patients start of the rucaparib administration (i.v. infusion (day 10) or received lead-in doses of i.v. and oral rucaparib on days 10 oral (days 5, 1, and 14)). On cycle 1 days 10 and 5, samples and 5, respectively, followed by carboplatin (AUC3, 4, or 5) on were also obtained 48 h after the start of rucaparib administration. day 1 and oral rucaparib on days 1–14 of every 21-day treatment Rucaparib concentration was determined using liquid chromato- cycle. The i.v. lead-in dose of rucaparib was discontinued once graphy with tandem mass spectrometry. The PK assay was sufficient bioavailability data for oral rucaparib were available. The validated by York Bioanalytical Solutions (York, UK) in accor- starting dose of 80 mg oral rucaparib was based on the safety 2 dance with the US Food and Drug Administration’s Bioanalytical established with up to 24 mg m i.v. rucaparib in combination Method Validation Guidance for Industry and Crystal City III with chemotherapy and an oral bioavailability of 36%. The Conference (US Food and Drug Administration, 2001; protocol prespecified dose cohorts of 80, 120, and 180 mg oral Viswanathan et al, 2007; Fast et al, 2009). The PK concentration rucaparib, after which rucaparib was to be escalated in 50% analysis population was defined as all treated patients who had at increments. Additional doses of 240 and 360 mg were subsequently least one concentration measurement in at least one treatment evaluated. Similarly, carboplatin dosing began at AUC3, with a period (cycle 1). The PK parameter analysis population was plan to escalate to AUC5 once the MTD of rucaparib was defined as all treated patients who had at least one of the PK established; however, escalation was modified to evaluate AUC4 parameters of interest in at least one treatment period (cycle 1). carboplatin before escalating to AUC5. Patients discontinuing Standard plasma PK parameters for rucaparib were estimated carboplatin could continue to receive oral rucaparib. using noncompartmental methods and included: maximum Safety and efficacy assessments. Safety assessments included plasma drug concentration (Cmax); area under the plasma concen- collection of adverse events (AEs) and serious AEs (defined by tration time curve from time 0 to the last sampling time with National Cancer Institute Common Terminology Criteria for measurable values (AUC0–t) and from time 0 to 24 h (AUC0–24); Adverse Events version 3.0; Pedersen et al, 2013), as well as vital and half-life (t1/2). Plasma clearance or apparent plasma clearance signs, physical examination, 12-lead electrocardiogram, laboratory and steady-state volume of distribution were calculated for assessments, and verification of concurrent medications. Safety rucaparib. The oral bioavailability of rucaparib was calculated as variables and demographic data were presented descriptively. the ratio of dose-normalised AUC0–t or AUCinf (data permitting) The safety analysis set included all enrolled patients who started determined using oral rucaparib PK data collected on cycle 1 day treatment. 5 to that determined using the i.v. PK data collected on cycle 1 Dose-limiting toxicities (DLTs) were defined as any of the day 10. Pharmacokinetic parameters were summarised with the following occurring during cycle 1: grade 4 neutropenia lasting X7 geometric mean and the coefficient of variation (CV). The ratio days; febrile neutropenia; grade 3 thrombocytopenia lasting X7 of Cmax and AUC0–24 of rucaparib administered in combination days with bleeding or grade 4 thrombocytopenia lasting 43 days; with chemotherapies to those of rucaparib alone was calculated grade X3 toxicity despite the use of adequate/maximal medical and summarised, with mean and CV% to evaluate the effect interventions and/or prophylaxis as dictated by local institutional of chemotherapies on the PK of rucaparib for both the i.v. dose clinical practices or the judgement of the investigator; grade 2 (day 10) and oral dose (day 5). Additional PK parameters neurotoxicity that did not recover to grade p1 within 2 weeks of examined and analyses performed are described in the planned dose; toxicities that resulted in a delay of 414 days in Supplementary Methods. initiation of cycle 2 dosing; or toxicities that resulted in failure to deliver X80% of the assigned oral rucaparib doses. Initially, at least three patients were treated at each dose level. If RESULTS no DLT was observed, the dose was escalated for the next cohort of three patients. If a DLT was observed in one of the three patients, Patients and treatments. Eighty-five patients were enrolled at three additional patients were enrolled and treated at the same dose seven sites in the United Kingdom and France (Table 1). Median level. If no further DLT was observed, the next dose level was age was 55 years (range, 20–76 years), approximately two-thirds of opened. Dose escalation continued until DLTs were observed in at patients were female, and all had an ECOG Performance Status of

886 www.bjcancer.com | DOI:10.1038/bjc.2017.36 Phase I intravenous and oral rucaparib with chemo BRITISH JOURNAL OF CANCER

Table 1. Patient demographics and disease characteristics Arm B, i.v. Arm C, i.v. Arm D, i.v. Arm A, i.v. rucaparib þ rucaparib þ rucaparib þ Arm A, rucaparib þ carboplatin/ cisplatin/ epirubicin/ oral rucaparib þ carboplatin paclitaxel pemetrexed cyclophosphamide carboplatin All patients Variable (n ¼ 18) (n ¼ 13) (n ¼ 16) (n ¼ 5) (n ¼ 33) (N ¼ 85) Median age (range), years 51.5 (23–68) 61.0 (39–69) 50.5 (32–68) 41.0 (32–53) 61.0 (20–76) 55.0 (20–76)

Gender, n (%) Female 11 (61.1) 7 (53.8) 10 (62.5) 4 (80.0) 23 (69.7) 55 (64.7) Male 7 (38.9) 6 (46.2) 6 (37.5) 1 (20.0) 10 (30.3) 30 (35.3)

Race, n (%) Asian 0 0 1 (6.3) 0 0 1 (1.2) Black 1 (5.6) 1 (7.7) 0 0 0 2 (2.4) White 17 (94.4) 12 (92.3) 15 (93.8) 5 (100.0) 33 (100.0) 82 (96.5) ECOG PS, n (%) 0 7 (38.9) 6 (46.2) 6 (37.5) 5 (100.0) 16 (48.5) 40 (47.1) 1 11 (61.1) 7 (53.8) 10 (62.5) 0 17 (51.5) 45 (52.9) Primary cancer diagnosis, n (%) Breast 7 (38.9) 1 (7.7) 4 (25.0) 4 (80.0) 6 (18.2) 22 (25.9) Ovarian/peritoneal 2 (11.1) 1 (7.7) 2 (12.5) 0 10 (30.3) 15 (17.6) Lung 1 (5.6) 2 (15.4) 1 (6.3) 1 (20.0) 3 (9.1) 8 (9.4) Pancreas 0 0 2 (12.5) 0 2 (6.1) 4 (4.7) Rectal 3 (16.7) 0 0 0 1 (3.0) 4 (4.7) Unknown primary 1 (5.6) 0 0 0 0 1 (1.2) Othera 4 (22.2) 9 (69.2) 7 (43.8) 0 11 (33.3) 31 (36.5) BRCA1 test results, n (%) Positive 2 (11.1) 1 (7.7) 2 (12.5) 0 2 (6.1) 7 (8.2) Negative 3 (16.7) 0 0 3 (60.0) 3 (9.1) 9 (10.6) Unknown 0 0 0 0 2 (6.1) 2 (2.4) Not tested 13 (72.2) 12 (92.3) 14 (87.5) 2 (40.0) 26 (78.8) 67 (78.8)

BRCA2 test results, n (%) Positive 2 (11.1) 0 0 0 1 (3.0) 3 (3.5) Negative 1 (5.6) 1 (7.7) 2 (12.5) 3 (60.0) 4 (12.1) 11 (12.9) Unknown 1 (5.6) 0 0 0 1 (3.0) 2 (2.4) Not tested 14 (77.8) 12 (92.3) 14 (87.5) 2 (40.0) 27 (81.8) 69 (81.2)

Median no. of prior anticancer 2.5 (1, 5) 2.0 (1, 6) 2.0 (1, 6) 3.0 (2, 5) 3.0 (1, 7) 3.0 (1, 7) therapies (min, max) Abbreviations: ECOG PS ¼ Eastern Cooperative Oncology Group Performance Status; i.v. ¼ intravenous. a Primary cancer diagnosis sites, including: appendix (n ¼ 2), colon (n ¼ 2), endometrium (n ¼ 2), pleura (n ¼ 2), stomach (n ¼ 2), abdomen (n ¼ 1), adrenal glands (n ¼ 1), back (n ¼ 1), bladder (n ¼ 1), oesophagus (n ¼ 1), ear (n ¼ 1), face (n ¼ 1), forearm (n ¼ 1), gastroesophageal junction (n ¼ 1), left leg (n ¼ 1), liver (n ¼ 2), prostate (n ¼ 1), shoulder (n ¼ 1), skin (n ¼ 1), testes (n ¼ 1), and not available (n ¼ 5).

0 or 1. Of the 85 patients, 22 (25.9%) had breast cancer, 15 (17.6%) 9.1%), no longer willing to participate in the study (2 patients, 6.1%), had ovarian/peritoneal cancer, 8 (9.4%) had lung cancer, 4 (4.7%) and other (5 patients, 15.2%). each had pancreatic or rectal cancer, 31 (36.5%) had other primary Dose-limiting toxicity and maximum tolerated dose. In arm A cancers, and 1 (1.2%) patient had a carcinoma of unknown (oral rucaparib), no patients experienced a DLT at doses up to primary origin. The BRCA test results were unavailable for most 360 mg rucaparib in combination with AUC4 carboplatin. The first patients (78.8% and 81.2% of patients did not undergo BRCA1 or three patients who received 360 mg rucaparib in combination with BRCA2 testing, respectively). The median number of prior AUC5 carboplatin experienced dose interruptions associated with anticancer therapies was three (range, 1–7). neutropenia, although these were grade 3 and did not meet the All patients had discontinued the study as of 2 April 2014. The p protocol-specified definition of a DLT. Therefore, a decision was median number of cycles initiated was 5 (range, 1–7) in arm A (i.v. made to enrol an additional three patients to further evaluate the rucaparib; n ¼ 18), 4 (range, 1–31) in arm A (oral rucaparib; n ¼ 33), safety and tolerability of this dose combination. Dose-limiting 4 (range, 1–6) in arm B (n ¼ 13),4(range,1–7)inarmC(n ¼ 16), toxicities of grade 4 thrombocytopenia and grade 4 neutropenia and 1 (range, 1–4) in arm D (n ¼ 5). Eight of 18 (44.4%) patients were observed in the first two patients treated, and thus the from arm A (i.v. rucaparib) and 17 of 33 (51.5%) patients from arm A third additional patient was not enrolled. The rucaparib dose was X (oral rucaparib) had one or more delays ( 1 week) between deescalated to 240 mg and three patients were treated. One patient treatment cycles. These occurred between cycles 1 and 2 in 1 (5.6%) experienced a DLT (grade 4 thrombocytopenia), and thus an patient in arm A (i.v. rucaparib) and 9 (27.3%) patients in arm A (oral additional three patients were enrolled. None of these three rucaparib). Four of 18 (22.2%) patients from arm A (i.v. rucaparib) additional patients had a DLT. Therefore, AUC5 carboplatin and had a dose reduction of carboplatin; 8 of 33 (24.2%) patients from 240 mg once daily (q.d.) oral rucaparib was declared the MTD. arm A (oral rucaparib) had a dose reduction, including 6 (21.2%) of Dose-limiting toxicities were also reported in one patient in arm carboplatin, 1 (3.0%) of rucaparib, and 1 (3.0%) of both drugs. Across B who was receiving 36 mg rucaparib, 306 mg paclitaxel, and all cohorts, 76 (89.4%) discontinued treatment with the following as 610 mg carboplatin (grade 3 diarrhoea and grade 3 nausea) and in the primary reason: objective progression or relapse (42 patients, one patient in arm C who was receiving 12 mg rucaparib, 900 mg 55.3%), AE (14 patients, 18.4%), global deterioration of health status pemetrexed, and 135 mg cisplatin (grade 3 fatigue, grade 4 (8 patients, 10.5%), no longer willing to participate in the study leukopenia, and grade 4 neutropenia). Because of a decision to (5 patients, 6.6%), and other (7 patients, 9.2%). Specifically, in arm A discontinue recruitment to the i.v. rucaparib arms during the (oral rucaparib; n ¼ 33) patients discontinued treatment primarily study, no MTD was determined for arms A (i.v. rucaparib), because of objective progression or relapse (18 patients, 54.5%), global B, C, and D that evaluated i.v. rucaparib in combination with deterioration of health status (5 patients, 15.2%), AE (3 patients, chemotherapy. www.bjcancer.com | DOI:10.1038/bjc.2017.36 887 BRITISH JOURNAL OF CANCER Phase I intravenous and oral rucaparib with chemo

Table 2. Treatment-emergent adverse events of any grade reported in 420% of patients in any treatment group

Arm A, oral rucaparib þ carboplatin (n ¼ 33) n (%) Arm A, i.v. Arm B, i.v. Arm C, i.v. Arm D, i.v. rucaparib þ rucaparib þ rucaparib þ rucaparib þ carboplatin carboplatin/ cisplatin/ epirubicin/ (n ¼ 18), paclitaxel pemetrexed cyclophosphamide Any Grade All patients Event n (%) (n ¼ 13), n (%) (n ¼ 16), n (%) (n ¼ 5), n (%) grade X3 (N ¼ 85), n (%) Nausea 14 (77.8) 7 (53.8) 10 (62.5) 4 (80.0) 23 (69.7) 4 (12.1) 58 (68.2)

Fatigue 14 (77.8) 4 (30.8) 14 (87.5) 1 (20.0) 20 (60.6) 2 (6.1) 53 (62.4)

Constipation 10 (55.6) 5 (38.5) 9 (56.3) 1 (20.0) 17 (51.5) 1 (3.0) 42 (49.4)

Vomiting 8 (44.4) 5 (38.5) 8 (50.0) 1 (20.0) 16 (48.5) 4 (12.1) 38 (44.7) Anaemia 6 (33.3) 2 (15.4) 8 (50.0) 0 18 (54.5) 4 (12.1) 34 (40.0)

Neutropenia 8 (44.4) 7 (53.8) 8 (50.0) 0 11 (33.3) 7 (21.2) 34 (40.0)

Diarrhoea 7 (38.9) 5 (38.5) 9 (56.3) 1 (20.0) 11 (33.3) 1 (3.0) 33 (38.8)

Thrombocytopenia 6 (33.3) 3 (23.1) 5 (31.3) 0 15 (45.5) 9 (27.3) 29 (34.1)

Decreased appetite 5 (27.8) 0 4 (25.0) 2 (40.0) 12 (36.4) 0 23 (27.1)

Abdominal pain 3 (16.7) 3 (23.1) 1 (6.3) 0 12 (36.4) 2 (6.1) 19 (22.4)

Headache 5 (27.8) 2 (15.4) 4 (25.0) 1 (20.0) 7 (21.2) 0 19 (22.4)

Dyspnoea 5 (27.8) 1 (7.7) 5 (31.3) 1 (20.0) 7 (21.2) 2 (6.1) 19 (22.4) Cough 2 (11.1) 0 6 (37.5) 0 8 (24.2) 0 16 (18.8)

Lethargy 1 (5.6) 6 (46.2) 1 (6.3) 0 7 (21.2) 0 15 (17.6)

Back pain 3 (16.7) 1 (7.7) 1 (6.3) 0 10 (30.3) 1 (3.0) 15 (17.6)

Alopecia 2 (11.1) 10 (76.9) 2 (12.5) 0 1 (3.0) 0 15 (17.6)

Stomatitis 4 (22.2) 6 (46.2) 1 (6.3) 1 (20.0) 2 (6.1) 0 14 (16.5)

Pyrexia 3 (16.7) 1 (7.7) 3 (18.8) 2 (40.0) 5 (15.2) 0 14 (16.5)

Dyspepsia 2 (11.1) 2 (15.4) 4 (25.0) 0 4 (12.1) 0 12 (14.1)

Oral candidiasis 1 (5.6) 2 (15.4) 6 (37.5) 1 (20.0) 1 (3.0) 0 11 (12.9) Arthralgia 2 (11.1) 3 (23.1) 4 (25.0) 0 2 (6.1) 0 11 (12.9)

Neuropathy peripheral 0 7 (53.8) 3 (18.8) 0 0 0 10 (11.8)

Insomnia 1 (5.6) 0 5 (31.3) 0 3 (9.1) 0 9 (10.6)

Abdominal pain upper 2 (11.1) 1 (7.7) 0 2 (40.0) 3 (9.1) 1 (3.0) 8 (9.4)

Epistaxis 1 (5.6) 0 5 (31.3) 0 0 0 6 (7.1)

Tachycardia 2 (11.1) 0 4 (25.0) 0 0 0 6 (7.1)

Asthenia 0 0 0 4 (80.0) 0 0 4 (4.7)

Influenza-like illness 0 0 4 (25.0) 0 0 0 4 (4.7) Abbreviation: i.v. ¼ intravenous.

Adverse events. All except one patient experienced an AE during the Pharmacokinetics. Rucaparib exposure increased approximately study. Adverse events occurring in 420% of patients in any treatment dose proportionally when given orally or intravenously (Supple- group are summarised in Table 2. Across the treatment arms, AEs mentary Tables S2–S5). On study day 14, the steady-state AUC0–24 were generally grade 1 or 2 in severity. The most common AEs (with increased by an average of 61%, with no change in t1/2 compared X30% incidence in all patients) across groups were gastrointestinal with a single dose. Regardless of the administration route, the dose- E events (i.e., nausea, constipation, vomiting, and diarrhoea), fatigue, independent t1/2 was 17 h as observed in patients from arm A and events related to myelosuppression (i.e., anaemia, neutropenia, (oral rucaparib) who received 27 mg i.v. rucaparib on day 10 and thrombocytopenia). Grade X3 AEs were reported in 64 of and 80 mg oral rucaparib on day 5 (Figure 2). Rucaparib 85 patients (75.3%), the most frequent of which were neutropenia demonstrated good absorption, with a dose-independent mean (23 patients, 27.1%), thrombocytopenia (16 patients, 18.8%), fatigue oral bioavailability of 36% in the fasted state. Rucaparib oral PK (11 patients, 12.9%), anaemia (10 patients, 11.8%), nausea (6 patients, was not affected by coadministration of AUC3 to AUC5 7.1%), and the following in 5 patients (5.9%) each: vomiting, carboplatin (Table 3). No apparent impact on i.v. rucaparib PK g-glutamyltransferase increased, and dyspnoea. Myelosuppression was observed with coadministration of carboplatin þ paclitaxel, was managed through transfusion or supportive medication when cisplatin þ pemetrexed, or epirubicin þ cyclophosphamide (Table 3). necessary; one patient (in arm C) received granulocyte colony- stimulating factor in response to grade 2 neutropenia. Treatment- Tumour response. Tumour response data were available for 77 of related AEs, as assessed by investigators, were reported in 94.1% of 85 patients. Across all cohorts, 1 patient (1.2%) with breast cancer patients (Supplementary Table S1). achieved a confirmed complete response (CR) and 9 patients Across treatment arms, 22 patients (25.9%) discontinued treatment (10.6%) achieved a partial response (PR) that was confirmed in 7 because of AEs that included neutropenia (3 patients, 3.5%), thrombo- patients (Table 4). Forty-three patients (50.6%) achieved stable cytopenia (2 patients, 2.4%), and platinum hypersensitivity (2 patients, disease (SD). Among patients with available data, across all 2.4%). While on study, 6 patients (7.1%) died of disease progression cohorts, the disease control rate (CR, PR, or SD for X12 weeks) that was assessed as unrelated to study drug. was 68.8%. Three of 33 patients (9.1%) receiving oral rucaparib in

888 www.bjcancer.com | DOI:10.1038/bjc.2017.36 Phase I intravenous and oral rucaparib with chemo BRITISH JOURNAL OF CANCER

1000 i.v. rucaparib: 27 mg (day −10) Oral rucaparib: 80 mg (day −5)

100 ) –1 (ng ml

10 Geometric mean plasma rucaparib concentration 1 0 6 12 18 24 30 36 42 48 Time post dose (h)

Figure 2. Plasma rucaparib concentration–time profile following i.v. or oral administration. Graph shows the geometric mean plasma concentration of rucaparib in patients in arm A (oral rucaparib) (n ¼ 4) who received i.v. and oral doses on days 10 and 5, respectively.

Table 3. Effect of carboplatin on oral rucaparib PK parameters and of chemotherapy on i.v. rucaparib PK parameters

Ratio of rucaparib PK parameters,a mean (CV%)

Cmax AUC0–24 Oral rucaparib Carboplatin dose AUC3 (n ¼ 15) 1.25 (46) 1.27 (37) AUC4 (n ¼ 3) 0.928 (24) 1.15 (51) AUC5 (n ¼ 11) 1.14 (59) 1.00 (48) Overall (n ¼ 29) 1.18 (49) 1.15 (87) Ratio of rucaparib PK parameters,b mean (CV%) Cmax AUC0–24 i.v. rucaparib Chemotherapy Carboplatin (n ¼ 6) 1.03 (16) 1.02 (15) Carboplatin þ paclitaxel (n ¼ 6) 0.917 (16) 0.86 (8) Cisplatin þ pemetrexed (n ¼ 8) 0.853 (42) 0.959 (20) Epirubicin þ cyclophosphamide (n ¼ 5) 0.968 (29) 0.916 (34)

Abbreviations: AUC ¼ area under the concentration time curve; AUC0–24 ¼ AUC for time 0 to 24 h; Cmax ¼ maximum plasma drug concentration; CV ¼ coefficient of variation; i.v. ¼ intravenous; PK ¼ pharmacokinetic. a Ratio of rucaparib PK parameter on day 1/day 5 with single oral dose of rucaparib (80, 120, 180, 240, and 360 mg) on day 5 and single oral dose of rucaparib (80, 120, 180, 240, and 360 mg) followed 1.5 h later with 30 min i.v. infusion of carboplatin (AUC3, AUC4, or AUC5) on day 1. b Ratio of rucaparib PK parameter on day 1/day 10 with i.v. dose of rucaparib (12, 18, or 24 mg) on day 10 and i.v. rucaparib plus i.v. chemotherapy on day 1; for AUC4, n ¼ 2 for AUC ratio; for overall, n ¼ 28 for AUC ratio.

combination with carboplatin had a confirmed PR. These included of dose, all of which are desirable characteristics for an oral agent. a patient with ovarian/peritoneal cancer (BRCA1 mutation, BRCA2 These PK findings with oral rucaparib are consistent with results wild type) who had a PR for 7 months, a second patient with from the phase I portion of an ongoing phase I–II study evaluating ovarian/peritoneal cancer (BRCA1 and BRCA2 wild type) who had single-agent oral rucaparib in patients with advanced solid a PR for 5 months, and a patient with breast cancer (BRCA1 tumours (Kristeleit et al, 2014). Pharmacokinetic exposure to oral mutation, BRCA2 not tested) who had a PR for 3 months. None of rucaparib was not changed by carboplatin coadministration. these patients had received prior PARP inhibitor therapy. When used in combination with AUC5 carboplatin, the i.v. rucaparib doses of 12, 18, and 24 mg evaluated were approxi- mately equivalent to oral rucaparib doses of 33, 50, and 67 mg, DISCUSSION respectively, representing 14%, 21%, and 28% of the MTD of 240 mg oral rucaparib. This phase I study demonstrated that oral rucaparib can be safely As anticipated with the concurrent administration of chemo- combined with a clinically relevant dose of carboplatin in patients therapeutic agents with rucaparib, myelosuppression (anaemia, with an advanced solid tumour. The MTD and recommended dose neutropenia, and thrombocytopenia) was commonly reported. for the combination is 240 mg q.d. rucaparib on days 1–14 with Myelosuppression is a known toxicity associated with a high AUC5 carboplatin on day 1 in 21-day cycles. dose of PARP inhibitors and is also often observed with many Oral rucaparib demonstrated dose-proportional kinetics and a chemotherapy regimens (Sandhu et al, 2013; Plummer et al, 2014; E long t1/2 ( 17 h) with good oral bioavailability (36%) independent Kaufman et al, 2015; Shapira-Frommer et al, 2015). In our study, www.bjcancer.com | DOI:10.1038/bjc.2017.36 889 BRITISH JOURNAL OF CANCER Phase I intravenous and oral rucaparib with chemo

Table 4. Investigator-assessed objective tumour response Arm A, i.v. Arm B, i.v. rucaparib þ Arm C, i.v. rucaparib þ Arm D, i.v. rucaparib þ Arm A, oral rucaparib þ carboplatin/ cisplatin/ epirubicin/ rucaparib þ All patients

a carboplatin paclitaxel (n ¼ 13), pemetrexed cyclophosphamide carboplatin (N ¼ 85), Best response (n ¼ 18), n (%) n (%) (n ¼ 16), n (%) (n ¼ 5), n (%) (n ¼ 33), n (%) n (%) Complete response 0 0 1 (6.3) 0 0 1 (1.2)

Partial response 3 (16.7) 1 (7.7) 2 (12.5) 0 3 (9.1) 9 (10.6)

Stable disease 9 (50.0) 8 (61.5) 7 (43.8) 1 (20.0) 18 (54.5) 43 (50.6)

Progressive disease 5 (27.8) 3 (23.1) 3 (18.8) 4 (80.0) 9 (27.3) 24 (28.2)

Missing 1 (5.6) 1 (7.7) 3 (18.8) 0 3 (9.1) 8 (9.4) Abbreviation: i.v. ¼ intravenous. a According to Response Evaluation Criteria in Solid Tumor version 1.1. thrombocytopenia and neutropenia were DLTs and also the most carboplatin had a clinical response; further work investigating this common severe toxicities reported across all treatment arms. combination may be warranted. Myelosuppression was also observed in 54% of patients treated with the combination of i.v. rucaparib and temozolomide in another study (Plummer et al, 2013). The combination of the PARP inhibitor ACKNOWLEDGEMENTS olaparib with chemotherapy, including carboplatin, has also been associated with substantial hematologic toxicity in phase I studies of WethankthestaffoftheBelfastCityHospital;BeatsonWestof patients with an advanced solid tumour (Khan et al, 2011; Rajan et al, Scotland Cancer Centre, Glasgow; Churchill Hospital, Oxford; Royal 2012; Samol et al, 2012; Dent et al, 2013; Lee et al, 2014a). Marsden Hospital, London; Guy’s Hospital, London; Institut Curie, Rucaparib exhibited clinical activity in combination with Paris; and the Northern Centre for Cancer Care, Newcastle. Above all, chemotherapy in this study of heavily pretreated patients with we particularly thank our patients, their families, and friends for their advanced malignancies. More than two-thirds of all patients in the support and participation in this trial. This study was funded by Clovis study had stable disease or better, and this is notable because Oncology, Inc., and Cancer Research UK and the UK Department of patients were not preselected for HRD (only 10 of 85 patients were Health funding for the UK Experimental Cancer Medicine Centre known to harbour a BRCA mutation). Of patients who received Network (to RHW, TRJE, MRM, LRM, JS, and RP). Writing and oral rucaparib and carboplatin, 63.6% achieved disease control editorial assistance funded by Clovis Oncology, was provided by Tim for X12 weeks, and PRs were reported in 3 patients with ovarian Lohret, Nathan Yardley, and Shannon Davis of Ashfield Healthcare or breast cancer, 2 of whom had a known BRCA mutation. Communications (Middletown, CT, USA). The benefits of inhibiting PARP in BRCA-mutated ovarian or breast cancer are well documented (Fong et al, 2009; Audeh et al, 2010; Tutt et al, 2010; Kaye et al, 2012; Sandhu et al, 2013; Lee et al, CONFLICT OF INTEREST 2014b). As a single agent, oral rucaparib has demonstrated activity against BRCA-mutated ovarian and breast cancer RHW has received an honorarium from Clovis Oncology for (Shapira-Frommer et al, 2015; Drew et al, 2016; Swisher et al, attending an advisory board relating to rucaparib. The institution 2017) and is currently being evaluated in phase III studies as both of TRJE has received reimbursement of study costs for this clinical maintenance and treatment therapy for patients with relapsed, trial and an honorarium from Clovis Oncology for his participa- high-grade ovarian cancer (ARIEL3 (NCT01968213) and ARIEL4 tion in an advisory board for another compound. MRM, LRM, JS, (NCT02855944)). VD, and PR have no conflict of interest to declare. HG is an When used in combination with carboplatin, the dose of rucaparib employee of Clovis Oncology. SJ-T was an employee of Clovis (240 mg q.d.) is lower than the MTD of single-agent rucaparib Oncology at the time of the study. SG is an employee of Clovis (600 mg twice daily). The lower dose of rucaparib in the combination Oncology. RP has received honoraria for attending advisory boards fits with prior studies demonstrating a synergistic effect with relating to rucaparib, is named on a patent of use for rucaparib for combinations of PARP inhibitors and DNA-damaging agents at which her institution will receive milestone payments, and has lower doses (Calabrese et al, 2004; Donawho et al, 2007; Thomas received research funding relating to this agent. et al, 2007; Ihnen et al, 2013). Given that platinum-based chemotherapies increase the burden of DNA damage in cells, the addition of PARP inhibition increases the cytotoxicity of these agents REFERENCES by preventing repair of damaged DNA. 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